Cancer of the prostate is the second most common malignancy in men and is the third most common cause of cancer death in men older than age 55. The cause is unknown, but hormonal factors appear to play a role in the development of prostatic cancer. The disease does not occur in eunuchs castrated before puberty, and its incidence is low in patients with hyper-estrogenism due to liver cirrhosis. Most cases is diagnosed after the age of 50 years, but they can be seen in younger adults. Total prostatoseminovesi-colectomy is the oldest treatment for carcinoma of the prostate. The operation may cause impotence and has its clearest indication only in stage B disease. Radiation therapy has major chronic complications after full courses of treatment and include impotence, chronic proctitis, rectal strictures, rectal fistulas and rectal bleeding. Additionally, current data suggest that radiotherapy may be less curative than radical prostatectomy. Androgen deprivation by means of bilateral orchiectomy, diethylstilbestrol therapy or combined orchiectomy plus diethylstilbestrol has been the standard form of treatment for carcinoma of the prostate for many years. However, recent prospective studies have not demonstrated a clear cut beneficial effect of this type of treatment. Furthermore death from cardiovascular disease appear to be more frequent in patients treated with large doses of diethylstilbestrol. Complete response to ordinary chemotherapy (e.g. estramustine phosphate, prednimusitne and cisplatin) is rare and only one-tenth of stage D patients have an objective partial response. Taken together, therefore, the treatment possibilities for this common malignancy is poor.
Centchroman is a non-steroidal compound known to have antiestrogenic activity. It is in use in India as an oral contraceptive (see, for example, Salman et al., U.S. Pat. No. 4,447,622; Singh et al., Acta Endocrinal (Copenh) 126 (1992), 444-450; Grubb, Curr Opin Obstet Gynecol 3 (1991), 491-495; Sankaran et al., Contraception 9 (1974), 279-289; Indian Patent Specification No. 129187). Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int J Cancer 43 (1989), 781-783. Recently, centchroman as a racemate has been found as a potent cholesterol lowering pharmaceutical expressed by a significant decrease of the serum concentrations (S. D. Bain et al., J Min Bon Res 9 (1994), S 394).
U.S. Pat. No. 5,453,442 describes methods of lowering serum cholesterol and inhibiting smoother muscle cell proliferation in humans and inhibiting uterine fibroid disease and endometriosis in women by administering compounds of formula I as shown therein. Furthermore U.S. Pat. No. 5,280,040 describes methods and pharmaceutical compositions for reducing bone loss using 3,4-diarylchromans and their pharmaceutically acceptable salts. There is no disclosure in the patents of using the compounds to treat prostatic carcinoma.
One object of the present invention is to provide compounds which can effectively be used in the treatment or prophylaxis of prostatic carcinoma.